This chapter is concerned with neurons whose cell bodies are located in the lumbosacral spinal cord and which contribute to the processing of tactile and pain sensations. Some glutamate-containing boutons were found to be postsynaptic to gamma-aminobutyric acid-containing boutons, suggesting that postsynaptic dorsal column neurons are controlled by presynaptic inhibition. Postsynaptic dorsal column neurons in the dorsal horn respond to stimuli applied to the skin. The spinocervical tract is another pathway that originates in the spinal cord gray matter and provides somatosensory information to the thalamus after a synaptic relay. Neurons of the spinocervical tract (SCT) are distributed in the dorsal horn in a somatotopically organized manner. Neurons of the SCT typically respond vigorously to weak mechanical stimuli although many have a convergent nociceptive input. The spinothalamic tract originates in the spinal cord and terminates largely in the contralateral thalamus, although there are some ipsilateral projections as well.

Spermatogonial stem cells (SSCs) are a subpopulation of undifferentiated spermatogonia located in a niche at the base of the seminiferous epithelium delimited by Sertoli cells and peritubular myoid (PM) cells. SSCs self-renew or differentiate into spermatogonia that proliferate to give rise to spermatocytes and maintain spermatogenesis. Glial cell line-derived neurotrophic factor (GDNF) is essential for this process. Sertoli cells produce GDNF and other growth factors and are commonly thought to be responsible for regulating SSC development, but limited attention has been paid to the role of PM cells in this process. A conditional knockout (cKO) of the androgen receptor gene in PM cells resulted in male infertility. We found that testosterone (T) induces GDNF expression in mouse PM cells in vitro and neonatal spermatogonia (including SSCs) co-cultured with T-treated PM cells were able to colonize testes of germ cell-depleted mice after transplantation. This strongly suggested that T-regulated production of GDNF by PM cells is required for spermatogonial development, but PM cells might produce other factors in vitro that are responsible. In this study, we tested the hypothesis that production of GDNF by PM cells is essential for spermatogonial development by generating mice with a cKO of the Gdnf gene in PM cells. The cKO males sired up to two litters but became infertile due to collapse of spermatogenesis and loss of undifferentiated spermatogonia. These studies show for the first time, to our knowledge, that the production of GDNF by PM cells is essential for undifferentiated spermatogonial cell development in vivo.

[11C]RO6924963, [11C]RO6931643, and [18F]RO6958948 have been reported as promising PET tracers for tau imaging based on in vitro studies and preclinical PET data (Honer, HAI 2015). Here we describe the first evaluation of these novel radiotracers in humans (ClinicalTrials.gov: NCT02187627). Seven amyloid PET positive Alzheimer's disease (AD) patients (4M:3F; 64-86 y; MMSE: 16-24), and 7 young healthy subjects (HS) (5M:2F; 25-38 y) each received 2 different tau tracers (1 additional HS was withdrawn). Dynamic 90 min scans were obtained after bolus injection of [11C]RO6924963 (4HS:2AD), [11C]RO6931643 (5HS:7AD), or [18F] RO6958948 (5HS:5AD). Arterial blood sampling was performed in 13/14 HS and 8/14 AD. Regions were defined on MRI, and PET data was quantified by plasma-reference graphical analysis (for VT) and target-cerebellum ratio (SUVR60-90). SUVRimages were also analyzed voxel-wise. Peak SUV values were approximately 3, 1.5 and 3.5 for [11C]RO6924963, [11C]RO6931643, and [18F]RO6958948, respectively. The retention of [11C]RO6931643 and [18F]RO6958948 in HS was much lower than that of [11C]RO6924963. For [11C]RO6931643 and [18F]RO6958948 (in AD), highest uptake was seen in the frontal (Fr), temporal (Tp), parietal (Pa), occipital (Oc), and fusiform (Fs) cortices, and the entorhinal area (ER). SUVR60-90 values ranged from 1.22 (L. Fr) to 1.55 (L. Oc) for [11C]RO6931643, and 1.39 (R.Fr) to 2.25 (L. Fs) for [18F]RO6958948, and VT ranged from 2.28 (R. ER) to 3.14 (L. Tp), and 3.98 (R. ER) to 5.62 (L. Tp), respectively. Regional analysis of SUVR and VT for [11C]RO6931643 and [18F]RO6958948 clearly allowed AD and HS to be distinguished. When compared to HS, the two tracers showed robust group effects (F>90; p=<10−6; two-way ANOVA) on SUVR and VT, and significant group differences (p<0.05 with Bonferroni correction; without overlap) in 6 of 12 regions for [11C]RO6931643 and 4 of 12 for [18F]RO6958948 (using SUVR). Voxel-wise analysis of SUVR revealed clusters of significantly higher uptake in AD compared to HS in Fs for [11C]RO6931643 (7 AD vs. 5 HS), and [18F]RO6958948 (5 AD vs. 5 HS). There were no radiolabelled metabolites nor defluorination of [18F]RO6958948.

Purpose - Inter-frame and intra-frame motion can adversely impact the performance of dynamic brain PET imaging. Only correcting the former can still result in degraded qualitative and quantitative performance. Meanwhile, patient motion introduces mismatches between transmission and emission data which may lead to incorrect attenuation and scatter compensation in the reconstruction process. As a result, the reconstructed dynamic images may carry erroneous estimates of radioactivity distribution. We seek a solution to this problem. Methods- We investigated the use of iterative deconvolution coupled with a proposed use of time-weighted averaging of motion-transformed transmission images to correct the transmission-emission mismatch artifacts in dynamic brain PET images. We performed simulations using real-patient motion profile acquired by the infrared Polaris Vicra motion tracking device which estimates 3-D motion transformations during PET acquisition. This was followed by frame-based motion correction employing three different transmission-emission alignment strategies: transmission image transformed by (1) mean motion transformation, (2) median motion transformation, and (3) the proposed time-weighted average of motion-transformed transmission images. Results- The results demonstrate that the proposed approach of using time-weighted averaging of motion transformed transmission images outperforms conventional methods by substantially reducing the transmission-emission mismatch artifacts in the reconstructed images. Coupled with an alignment of the reconstructed frames for inter-frame motion correction and a subsequent iterative deconvolution approach for intra-frame motion correction, the resulting motion compensated images showed superior quality, considerable reduction in error norm and enhanced noise-bias performance compared to conventional methods of transmission-emission mismatch compensation. The performance was consistent across different levels of intra-frame motion, and the algorithm was amenable to different framing schemes. Conclusion - In frame-based motion correction of dynamic PET images, it is feasible to achieve intra-frame motion compensation using time-weighted averaging of motion transformed transmission images coupled with a post-reconstruction iterative deconvolution procedure to compensate for intra-frame motion.

The pain system is the set of neural pathways responsible for mediating the sensations interpreted as pain. Sensory-discriminative aspects of pain originating from the body surface include coding for the precise quality, intensity, duration, and location of the sensory input. Pain arising from visceral organs and other deep structures of the body is usually poorly localized and has a different, dull aching quality. Neurons that signal the sensory-discriminative components of pain sensation encode these aspects of painful stimuli in a manner generally similar to that used by other sensory systems, such as the visual and auditory systems. However, pain more powerfully engages mechanisms of attention and arousal in limbic regions of the brain than is generally the case for vision and audition. The sense of pain is more often accompanied by strong motivational-affective responses, including emotional reactions (suffering, anxiety, depression), somatic and autonomic reflexes, and endocrine changes. This is especially true for visceral pain. The neural pathways that mediate the motivational-affective components of pain overlap to some extent those involved in pain sensation, but also include additional neural structures and pathways. A better understanding of many complex mechanisms and circuitries underlying sensory dysfunction gained through the study of animal models has translated into existing successful therapies. Focus on the neuroplasticity and dysfunctional mechanisms induced in chronic pain models is leading to the development of better future therapeutics.

Central modulation of serotonin and dopamine underlies efficacy for a variety of psychiatric therapeutics. ITI-007 is an investigational new drug in development for treatment of schizophrenia, mood disorders, and other neuropsychiatric disorders.

Using the α7-nAChR radiotracer, [18F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer.

The rewarding effects of nicotine are associated with activation of nicotine receptors. However, there is increasing evidence that the endogenous opioid system is involved in nicotine's rewarding effects. We employed PET imaging with [11C]carfentanil to test the hypotheses that acute cigarette smoking increases release of endogenous opioids in the human brain and that smokers have an upregulation of mu opioid receptors (MORs) when compared to nonsmokers. We found no significant changes in binding potential (BPND) of [11C]carfentanil between the placebo and the active cigarette sessions, nor did we observe differences in MOR binding between smokers and nonsmokers. Interestingly, we showed that in smokers MOR availability in bilateral superior temporal cortices during the placebo condition was negatively correlated with scores on the Fagerström Test for Nicotine Dependence (FTND). Also in smokers, smoking-induced decreases in [11C]carfentanil binding in frontal cortical regions were associated with self-reports of cigarette liking and wanting. Although we did not show differences between smokers and nonsmokers, the negative correlation with FTND corroborates the role of MORs in superior temporal cortices in nicotine addiction and provides preliminary evidence of a role of endogenous opioid signaling in frontal cortex in nicotine reward.

The primary objectives of this study were to assess the safety of [18F]flutemetamol injection and determine the level of association between the quantitative estimates of brain uptake of [18F]flutemetamol and the quantitative immunohistochemical (IHC) estimates of amyloid levels in cerebral cortex biopsies obtained during shunt placement in patients with normal pressure hydrocephalus (NPH).

UNLABELLED:We evaluated (-)-2-(6-[(18)F]fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane ((18)F-AZAN), a novel radiotracer that binds to α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. METHODS:We tested safety tolerability and test-retest reliability (n = 5) and proposed initial quantification of (18)F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the α4β2-nAChR-selective partial agonist varenicline. RESULTS:Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for (18)F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) using plasma reference graphical analysis, which showed excellent reproducibility of BPND (test-retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP(ND) values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n = 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of (18)F-AZAN brain uptake in smokers and varenicline-treated subjects. CONCLUSION:(18)F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity α4β2-nAChR in the living human brain.

Background and peripheral mechanisms of nociceptor sensitization characteristics and mechanisms of primary hyperalgesia mechanisms of secondary hyperalgesia role of central changes in hyperalgesia clinical aspects of hyperalgesia and future research directions.

Evidence from recent clinical studies has shown the benefits of SMBG plus a structured testing program (SMBG+STG) in non-insulin treated patients with T2DM. The Structured Testing Protocol (STeP) study found SMBG+STG can lead to improvements in glycemic control. This study assessed the cost-effectiveness of SMBG+STG versus SMBG alone from the Spanish health care system perspective in the context of recent studies of SMBG that have employed active education programs. A discrete event simulation model was developed to simulate the economic and health outcomes based on A1c changes related to using SMBG+STG or SMBG alone. Baseline A1c (8.4%) changes over 1 year (-1.2% and -0.9% for SMBG+STG versus SMBG alone), discontinuation and hypoglycemia rates were from the STeP study. Population and cost inputs were from published Spanish sources. Over a lifetime horizon (>30yrs), the model predicts: diabetes related complications (cardiovascular disease, stroke, amputations, end stage renal disease), hypoglycemia, life years (LYs) and quality adjusted life years (QALYs). Costs associated with events were estimated. Benefits and costs were discounted at 5%. Uncertainty in model estimates, such as changes in price per strip, treatment groups, program component, and A1c differences, was explored with sensitivity analyses. SMBG+STG was predicted to reduce complications and associated costs. Lowering A1c and consequent complications prevention with SMBG+STG translated into a dominant incremental cost-effectiveness ratio. Comparisons with a group not utilizing SMBG yielded similar results. In the long term, SMBG+STG is a cost-effective option compared to SMBG alone. An A1c reduction of 0.3% is a cost-effective outcome. Decison makers should consider designing programs to educate patients about SMBG+STG.